A family of novel mitochondrially-encoded peptides and their role in aging Abstract Mitochondria are involved in energy metabolism and apoptosis, and are central to multiple diseases, including diabetes, cancer, and neurodegeneration. Mitochondria contain hundreds of proteins, but the mitochondrial-chromosome only encodes 13 proteins. In 2001, humanin; a novel 24-amino-acid peptide encoded from the 16S ribosomal RNA region of the mtDNA, was described to be a potent neurosurvival factor. Almost at the same time we demonstrated that humanin binds and antagonizes the proapoptotic-molecule IGFBP-3. In preliminary unpublished data, we have shown that humanin activates a pro-survival signaling-cascade and demonstrated that it is a potent in vivo insulin sensitizer. We recently discovered that in addition to humanin, there are six additional ORFs within the 16S rRNA and we synthesized their corresponding peptides, which we named SHLPs (small humanin-like peptides). Initial characterization of the biological activity of the SHLPs 1-5 indicates that they are potent bioactive molecules acting to induce cell survival similarly to humanin, but with different temporal profiles, suggesting that these peptides act in concert. SHLP-6, has opposing actions, inhibiting cell growth. These observations suggest that the mitochondria may possess previously unappreciated roles in the regulation of metabolism and survival that occur via the synthesis of mitochondrial-derived peptides (MDPs). A bioinformatics scan of the mitochondrial chromosome indicates that there are over 100 additional ORFs throughout the mtDNA. This EUREKA Award project proposes to characterize the expression and specific functions of MDPs; and to try to functionally and genetically link MDPs to mitochondrially-related diseases of aging. Our approach will involve genomic and proteomic approaches in humans with exceptional longevity and in relevant mouse models of aging. We propose that the mitochondrial peptidome could explain important new aspects of mitochondrial biology and dysfunction with relevance to a aging. This line of research is a dramatic shift from the investigators previous work, and represents a innovative, high-risk project. of this research to public health All countries, and particularly the United States, are experiencing a growth in the numbers of elderly people in the population. By 2020 the world population of elderly people is expected to have trebled, with an estimated 700 million people aged 65 years and over of whom 70% will be in developing countries. Of particular significance is the growth of the oldest old in the population whose medical care and other needs have not been traditionally addressed. Opportunities for improving the health of elderly people have been limited. This is due to a variety of factors: negative images of ageing and concepts that health promotion and disease prevention in old age are not worthwhile; and, until relatively recently, neglect by the research community of common problems of old age. In particular diseases of aging, including neurodegeneration, metabolic syndrome, and various malignancies, affect the majority of the elderly and require a better understanding of the biological processes involved. Recent studies indicate that growth factors are central to various aging related processes affecting cell survival and senescence and growth factor related therapies have been proposed as possible approaches to the aging problem. In our proposed project we will study a family of novel growth and survival factors called SHLPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.